Hypertension is a complex disease process involving many pathophysiological changes. In this Program Project, the individual research topics focus on the theme that mechanistic cellular changes induced by genetic and environmental factors contribute to the abnormal control of blood pressure in hypertension. The strategy of the group is to monitor many relevant variables during the development of hypertension with the goal of defining the complete sequence of events from the introduction of an intervention (experimentally imposed or genetic) to the resultant elevation in blood pressure. Among these variables are alterations in neural and endocrine factors, cellular events and molecular and genetic characteristics. Six principal investigators from four departments (2 clinical and 2 pre-clinical) have joined to study these changes. Animal models will include genetically hypertensive rats and renal and mineralocorticoid hypertensive rats. In addition, a new model of hypertension produced by infusion of oleic and/or palmitic acid in rats will be characterized. Among the specific variables measured will be ion fluxes in vascular and endothelial cells, hormone levels and secretion (renin, aldosterone, catecholamine, insulin), vascular reactivity, ion channel activity. mRNA for specific proteins, enzyme activities and genetic associations. Research strategies will utilize the professional expertise and equipment described in two of three core units (Core 2, Animal; C3, Chemistry). Biostatistics support and scientific management will be coordinated through the Administrative Core (C1). From these integrated projects, a better understanding of the initiating factors of hypertension will emerge.